In the last few years, the use of biodegradable polymeric nanoparticles as carriers for the administration of drugs, especially by an oral route, has been developed. Nanoparticles are generally defined as solid particle type colloidal systems, with a size less than one micrometer, formed by natural or synthetic polymers. Depending on the process followed in their preparation, two types of structures can be obtained: nanospheres or nanocapsules. Nanospheres have a polymeric matrix type structure, in which the active ingredient is dispersed, whereas nanocapsules have a core containing the active ingredient, surrounded by a shell, such as a polymeric shell. Due to the high specific surface of these systems the active ingredient can also be adsorbed on the surface of the nanoparticular system.
The oral route is the most popular and attractive route for the administration of medicinal products. The use of this route is associated to a significant increase of the acceptance of the medication by the patient and with lower sanitary costs. However, an important number of drugs have a very low efficacy when they are administered by means of this route. This phenomenon can be due to one or several of the following factors which condition the oral bioavailability of a drug: (i) low permeability of the active molecule for traversing the mucosa (generally associated to hydrophilic drugs), (ii) low stability in the gastrointestinal environment (presence of extreme pH values, enzymes, etc.), (iii) incomplete release of the drug from the dosage form, (iv) low solubility of the active ingredient in the gastrointestinal environment (associated to hydrophobic drugs), and (v) presystemic metabolism.
On a number of occasions, nanoparticulate systems allow, significantly increasing the bioavailability of the biologically active molecule and, therefore, offering new administration strategies. The improvement of the bioavailability obtained after using these carriers can be explained by means of the ability of the polymeric nanoparticles for developing bioadhesive interactions with the gastrointestinal mucosa tract. Thus, when a nanoparticle suspension is administered orally, these carriers can interact and develop adhesive interactions with several components of the mucosa. Depending on certain physicochemical parameters (such as the nature of the polymer, size, surface charge or the presence of certain coatings or ligands in the carrier), the bioadhesive characteristics of the nanoparticles can vary and allow, in certain cases, reaching the enterocyte surface, and, possibly, developing bioadhesive interactions in very specific regions of the gastrointestinal tract. All these phenomena lead to (i) an increase of the residence time of the dosage form in close contact with the surface of the mucosa, or to (ii) a specific location of the carrier (with the drug substance) in a certain area. Once the nanoparticles are adhered to the mucosa, they can promote the absorption of the carried drug and its access to the systemic circulation by means of several mechanisms.
Illustrative examples of drugs the oral bioavailability of which increases by means of their encapsulation or association to nanoparticles include salmon calcitonin, furosemide, avarol, dicumarol, nifedipine, fluoropyrimidines, plasmids, etc.
Homo- and copolymers of lactic and glycolic acids (PLGA) are especially important as biodegradable polymers for manufacturing particulate systems since they have good tissue compatibility, are not toxic and have been used for many years as reabsorbable suture material. These (co)polymers are soluble in organic solvents, such as chloroform, dichloromethane, acetone and ethyl acetate and insoluble in aqueous media; however, they can capture water and swell to a greater or lesser extent, depending on their molecular weight and on their composition. Among the drawbacks of these polymers, it should be emphasized that PLGA can be rather hydrophobic compared to many of the antigens that it carries. Furthermore, both PLGA hydration and degradation are essential requirements for releasing the antigen during the erosion phase. This erosion causes a rather acidic microenvironment due to the accumulation of the polymer degradation products, lactic and glycolic acids; the pH can drop until the order of 2-3. In these conditions, the released proteins undergo hydrolysis and aggregation in the acidified medium and many antigens lose their antigenic capacity. Finally, their high cost could limit their use and would favor the search for other less expensive materials.
As an alternative to polyesters, nanoparticles prepared with other polymers have proven to be suitable for the oral administration of drugs. One of the most used polymers is chitosan. Chitosan is a polymer similar to cellulose coming from the deacetylation of the chitin, the main component of the exoskeleton of crustaceans. Chitosan can be formulated in nanoparticles of different sizes in which it has the drug incorporated. Chitosan particles can increase protein absorption in the mucosal surface, inducing a transient opening of the tight junctions. Furthermore, chitosan can have an immunomodulatory effect, stimulating in vitro cytokine production and improving the natural Th2/Th3 balance at the mucosa level in the absence of antigen.
The methyl vinyl ether and maleic anhydride copolymer (PVM/MA) [Gantrez®] has recently been proposed as a biodegradable material for producing nanoparticles (Arbos et al., J. Control. Release, 83 (2002) 321-330). These PVM/MA copolymers are widely used as thickeners, stabilizers of aqueous solutions, dental adhesive components, transdermal patches and in oral tablets. Among the main advantages of these polyanhydrides, their low cost, their low oral toxicity and the availability of functional groups that can easily react with molecules containing hydroxyl or amino groups should be emphasized (Arbos et al., J. Control. Release, 89 (2003) 19-30). Thus, in an aqueous medium, the anhydride group is hydrolyzed originating two carboxyl groups and this reaction allows easily binding ligands to the polymeric chain or to the surface of the prepared nanoparticles.
Cyclodextrins (CDs) are a group of cyclic oligosaccharides obtained by enzymatic starch degradation of. They are formed by α-1,4-glucopyranose units bound to one another, forming a frustoconical type structure with a hydrophobic internal cavity. CDs can contain more than 15 α-1,4-glucopyranose units, although the most abundant ones contain 6 (α-CD), 7 (β-CD) or 8 (γ-CD) α-1,4-glucopyranose units. In pharmaceutical applications, β-CD and its derivatives are the most used, particularly 2-hydroxypropyl-β-cyclodextrin (OH-β-CD). This CD has a high aqueous solubility, lower toxicity as well as a more hydrophobic cavity compared to the original compound (β-CD). The complexes formed by means of using cyclodextrins can provide the host molecule with stability and increased aqueous solubility, which can lead to increases of the bioavailability of this molecule (e.g. drug) and/or the reduction of side effects. Furthermore, the capacity to increase the loading capacity of liposomes and microparticles has been described in the literature. CDs can also modify the release profile of the encapsulated drug.
A number of antitumor agents are administered parenterally, which causes several problems. Among the main advantages involved in the oral administration of antitumor agents, the increase in the quality of life of the patients as well as the reduction of sanitary costs should be emphasized. This route of administration would allow a continuous exposure of cancer cells to the antitumor drug at a suitable and sustained concentration level, which can improve the therapeutic index and reduce side effects. However, most of these drugs (e.g. paclitaxel) have low bioavailability when administered orally.
Paclitaxel (Taxol®, Bristol Myers Squibb Company), a product extracted from the Taxus brevifolia tree, was described for the first time in 1971 and since 1993 it is the most used chemotherapeutic agent against cancer in the whole world. Paclitaxel acts at a cellular level promoting the polymerization of tubulin. The microtubules formed in the presence of paclitaxel are thus extraordinarily stable and non-functional, thus causing cell death by the dynamic and functional incapacity of microtubules for cell division. In Europe, this drug is indicated both as an individual agent and in combination with other oncological treatments for the treatment of ovarian cancer, breast cancer and non-small cell lung cancer, both advanced and metastatic.
The main drawback of this drug lies in its poor oral bioavailability due to its low aqueous solubility and mainly to the first-pass metabolism effect. After oral administration, paclitaxel is substrate of P-glycoprotein, as well as of other members of the ABC (ATP-binding cassette) superfamily, such as BCRP and MRP2. The protein transporter ABC superfamily plays a central role in the defense of the organism against toxic compounds and against some anti-cancer agents. Said proteins (P-glycoprotein, MRP2 and BCRP) are located in the apical area of the intestinal, hepatic and renal membranes, mediating the pumping of xenobiotics and toxins to the intestinal, biliary lumen and urine. Furthermore, both P-glycoprotein and MRP2 are located jointly together with CYP3A4, glutathione S-transferases and UDP-glucuronosyltransferases, which involves a synergistic action in regulating the oral bioavailability of the administered drugs.
Due to the foregoing, paclitaxel is currently formulated for its use in clinical practice and by an intravenous route in a carrier formed by Cremophor EL:ethanol (1:1). For the purpose of preventing and minimizing the toxic effects of Cremophor EL by an intravenous route and improving the therapeutic index of the drug, a new formulation based on encapsulating the drug in albumin nanoparticles called Abraxane® (Green et al. Annals of Oncology 17:1263-1268, 2006) has recently been marketed.
It is therefore necessary to develop drug administration systems which can increase, when administered orally, the bioavailability of a number of active ingredients, especially of those drugs with a lipophilic nature and/or which are a substrate of P-glycoprotein (e.g. paclitaxel). Advantageously, said administration systems should have bioadhesive properties, should have the capacity to incorporate variable amounts of lipophilic drugs, and, ideally, should be able to prevent the effect of P-glycoprotein on the transported drug. These objectives can be achieved by means of the nanoparticles provided by the present invention.